Physiology's Impact: Stop Ignoring the Obvious–SEX MATTERS!

Virginia M. Miller, Jane F. Reckelhoff, Gary C. Sieck

We live in the world of individualized medicine, where knowledge of the human genome is helping to guide specific diagnosis and clinical treatment at the individual level. Yet, all too often, we ignore the basic distinction of sex in our experiments and the evidence base for clinical practice. Indeed, consideration of sex differences should drive individualized medicine. Unfortunately, our journal Physiology has been just as blind to this major distinction as other biomedical journals. Over the past 10 years, we have published only three review articles that consider sex differences in physiology out of more than 550 review articles that we have published. As a community of physiologists and biomedical scientists, we must finally recognize that sex matters! The inquiring minds of physiologists need to know!

The International Union of Physiologists defines physiology as “the study of the functions and integrative processes of life at all levels of structural complexity between the molecular level and that of the whole organism. It includes all organisms, and frames function in evolutionary, environmental, ecological and behavioral contexts. It embraces a cross-disciplinary approach to modern science, through which physiologists aim to achieve translation of this knowledge into human health” (3). To comply with this definition requires that researchers who define themselves as physiologists consider “sex” as a critical variable to be included in the design of their experiments, selection of experimental material, interpretation of their results and in their critique of the literature.

Why? First and foremost, every cell has a sex determined by the presence of the complement of sex chromosomes. The non-gonadal functions directed by the sex chromosomes are as critical to the physiology of the organism as the gonadal development functions; some of these non-gonadal functions include innate immunity, regulation of sympathetic neurotransmission, androgen sensitivity, mitochondrial function, and apoptosis. Thus the sex of cells in culture, isolated tissues, as well as whole animals cannot be ignored if the physiologist wants to be thorough in his/her approach to the experimental design.

Second, sex steroids produced by gonads and programmed by chromosomes dictate genomic and non-genomic processes that affect cellular organizational (effects that are irreversible with removal of the gonads) and activational (effects that are reversible with removal of the gonads and replacement of sex hormones) cellular processes. Considered another way, the sex chromosomes in conjunction with sex hormones influence structure and function, i.e., integrative physiology. Thus “sex” is a basic variable in every physiological experiment and is the cornerstone for translation of basic physiological principles to human health and to individualized, evidence-based medicine.

Sex differences related to reproductive function have received attention in several past reviews in Physiology: erectile dysfunction (7), remodeling of the uterine vasculature during pregnancy (8), and factors contributing to the etiology of preeclampsia of pregnancy (11, 12).

Attention to sex differences in non-reproductive regulatory systems has received historically less attention than in reproductively oriented studies. Unfortunately, many classic studies that are still cited today as dogma were derived from experiments conducted in men. For example, Physiology of Man in the Desert by E. F. Adolf (Interscience Publishers, 1947) describes studies in young, healthy military volunteers in World War II. Today, inquiring minds want to know whether temperature, water, and electrolyte regulatory processes defined in young healthy men apply to women. Only two recent reviews in Physiology have addressed sex differences in renal function and regulation of the renin angiotensin systems (1, 14).

In the current issue of Physiology, a review by Hart and Charkoudian explores sex differences in the relationship between sympathetic outflow and peripheral resistance (2). This relationship may not be linear in women as once was defined for men, but, in fact, the relationship is nonlinear in young women and is modified by age and hormonal status. These observations have implications for development of new approaches to classification and treatment of autonomic-related vascular diseases, such as postural orthostatic hypotension (POTS) and Raynaud's disease, which have a female prevalence, not to mention the importance of development of sex-based treatment for hypertension, which is sadly absent from therapeutic guidelines at present.

The American Physiology Society's editorial policy requires the reporting of the sex of the experimental material as a condition of scientific excellence. As researchers, reviewers, and editors, we should be vigilant to ensure that the policy is enforced. As members of peer review panels, we can evaluate proposed research with a “sex and gender” lens to ensure that there is appropriate attention to how sex affects the scientific outcome (9).

Recently, the scientific community has directed attention toward reasons why the results of basic science experiments fail to be translated to the clinical arena (10). Most of the potential solutions have focused on statistical issues in experimental design and analysis ( Is this the answer? How can an investigator reproduce results from basic laboratory if the source of the experimental material is unknown? It is clear that gene expression varies by sex and hormonal status of the experimental material (46, 13). Therefore, analyzing data from mixed groups of men and women in human studies may mask an effect, especially if the particular response may be upregulated in one sex and downregulated in the other. Studying mechanisms in only one sex and assuming that the same systems apply to the other sex is not good science. Can we improve reproducibility in science? Can we hasten translation of basic science to application to human health? Yes, but first we must stop ignoring the obvious.

As physiologists, we can do better and lead the field in this important concept–SEX MATTERS!


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